Methamphetamine [METH (''speed'')] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METHtreated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL-and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs.] is a psychostimulant that is abused throughout the U.S. and the world. Its use can result in euphoria, decreased appetite, and increased alertness, whereas long-term abuse of METH can result in neuropsychiatric complications such as paranoia, coma, stroke, and even death (1, 2). The acute euphoric and intoxicating effects of the drug are thought to be related to the release of dopamine (DA), a neurotransmitter that is very abundant in the mammalian striatum (3). In contrast, the long-term changes that occur in human abusers might be due to neurotoxic or neurodegenerative effects of the drug on monoaminergic terminals (4, 5), abnormalities that have been replicated in animal models of METH toxicity (6). Recent animal studies have also suggested that METH can damage neuronal cell bodies located in the frontal cortex and striatum (6), abnormalities that might also have an impact on the clinical signs and symptoms observed with chronic abuse of the drug. These suggestions are supported by observations that recovery of indices of DA depletion is not associated with significant improvement in neuropsychological parameters in METH abusers (7) and by reports that METH abusers show metabolic abnormalities in other brain regions in addition to the striatum (8, 9). A recent postmortem study has also provided evidence of METH-induce...
Hematopoietic stem cell transplantation from HLA-matched sibling donors results in disease-free survival of >90% in patients with sickle cell disease (SCD); however, only approximately 18% of these patients have suitable donors available. Unrelated cord blood transplantation (UCBT) is one way to expand donor options for patients with severe SCD, but historically has been associated with high graft rejection rates (50% to 62%). We hypothesized that the addition of thiotepa to a previously tested reduced-intensity conditioning (RIC) regimen would support engraftment after UCBT in patients with SCD. Nine children (age 3 to 10 years) with cerebrovascular complications of SCD underwent 5-6/6 HLA-matched (A, B, and DRB1 loci) UCBT after conditioning with hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. A calcineurin inhibitor and mycophenolate mofetil were used for graft-versus-host-disease (GVHD) prophylaxis. With median follow up of 2.1 years (range, 1 to 4.2 years), 7 patients had sustained donor cell engraftment and are free of SCD, and 2 patients had autologous recovery. Acute GVHD (grade II-IV) and mild and moderate chronic GVHD developed in 3 patients, 2 patients, and 1 patient, respectively. At >2 years post-UCBT, 4 of 5 patients discontinued systemic immunosuppression. Seven patients had viral infections (cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, or adenovirus) and recovered. The 1-year overall survival and disease-free survival rates were 100% and 78%, respectively. Thus, this RIC regimen was able to achieve donor engraftment in the majority of patients. Future efforts will focus on further reducing rates of acute GVHD and viral infection.
MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL, during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL–driven AML, we tested whether Lin28b, a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL–driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.
The FLT3 Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3ITD simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3ITD can activate STAT5 signal transduction prior to birth, this signaling does not alter gene expression until hematopoietic progenitors transition from fetal to adult transcriptional states. Cooperative interactions between Flt3ITD and Runx1 mutations are also blunted in fetal/neonatal progenitors. Fetal/neonatal progenitors may therefore be protected from leukemic transformation because they are not competent to express FLT3ITD target genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.DOI: http://dx.doi.org/10.7554/eLife.18882.001
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